Antibotrytical pyrazolo-triazol-triones

ABSTRACT

A series of condensed heterocycles, more particularly condensates of triazolones with pyrazolones, which exhibit antibotrytical activity, are disclosed. A process for producing the new heterocycles, which are pyrozolo-triazol-triones, by reacting carbethoxy pyrazolones with isocyanates, in the presence of tertiary amines, is also disclosed.

THE PRIOR ART

Belgian Pat. No. 874,406 describes fungicidally activeN-aryl-1,3-oxyazolidin-2,4-diones substituted in position 5 with acarboxylic group, and having the general formula: ##STR1##

Fungicidally active derivatives of4-(3'-5'-dichlorophenyl)-1,2,4-triazolidindione are disclosed inJapanese Pat. No. 77/83562.

THE PRESENT INVENTION

An object of the present invention is to providepyrazolo[1,2,a]-[1,2,4]-triazol-1,3,5(2H)-triones which areantibotrytical and specifically active against Botrytis cynerea.

Another object is to provide a process for producing thepyrazolo-triazol-triones.

These and other objects are achieved by this invention in accordancewith which pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-triones endowed withexcellent antibotrytical activity and having the general formula##STR2## in which

R¹ is a C₁ -C₅ alkyl, phenyl optionally substituted by alkyl,trihaloalkyl, alkoxy, NO₂ or halogen, and particularly the group3,5-dihalophenyl; and

R² and R³

are obtained by reacting a carbethoxy pyrazolone of the general formula##STR3## in which R² and R³ have the same meaning as in formula (I),with an isocyanate of formula

    R.sup.1 --N═C═O

in an inert solvent, preferably an aromatic hydrocarbon such as benzene,in the presence of an equimolar amount of a tertiary amine, at atemperature comprised between room and the boiling temperature.

The reaction proceeds as follows: ##STR4##

Under these conditions, when the solvent is benzene, thepyrazolo-triazol-trione-derivative may precipitate as the reactionproceeds.

Since the isocyanate may react with the ethanol freed by the reaction,to yield the corresponding R¹ --NH--COO₂ H₅ carbamate, it is possible tohave the above-indicated reaction occur in two stages, by firstcondensing an equimolar quantity of isocyanate with the carbethoxypyrazolone at room temperature, in the presence of catalytic quantitiesof tertiary amine, and then, once the reaction has been completed, theremaining tertiary amine in order to attain the equimolar quantitynecessary for obtaining the triazolidinic ring closing, according to thefollowing reaction scheme: ##STR5##

The compounds shown in Table I, among others, were thus prepared, thestarting 2-ethoxycarbonyl-3-pyrazolidin-5-one being obtained by reactingthe substituted pyrazolone with ethyl chloroformate.

                                      TABLE I                                     __________________________________________________________________________     ##STR6##                                                                     Com-                                                                          pound                    SUBSTITUENTS     M.P.  CRYSTAL.                      No. DENOMINATION         R.sup.1   R.sup.2                                                                           R.sup.3                                                                          (°C.)                                                                        SOLVENT                                                                              FORMULA                __________________________________________________________________________    1   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               C.sub.6 H.sub.5                                                                         CH.sub.3                                                                          H  164-166                                                                             ethanol                                                                              C.sub.12 H.sub.9                                                              N.sub.3 O.sub.3            trione-2-phenyl-7-methyl                                                  2   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               4ClC.sub.6 H.sub.4                                                                      CH.sub.3                                                                          H  216-218                                                                             ethanol                                                                              C.sub.12 H.sub.8                                                              ClN.sub.3 O.sub.3          trione-2(4-chlorophenyl)-7-methyl                                         3   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3ClC.sub.6 H.sub.4                                                                      CH.sub.3                                                                          H  164-165                                                                             ethanol                                                                              C.sub.12 H.sub.8                                                              ClN.sub.3 O.sub.3          trione-2(3-chlorophenyl)-7-methyl                                         4   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3,4Cl.sub.2 C.sub.6 H.sub.3                                                             CH.sub.3                                                                          H  249-251                                                                             ethanol                                                                              C.sub.12 H.sub.7                                                              Cl.sub.2 N.sub.3                                                              O.sub. 3                   trione-2(3,4-dichlorophenyl)-7-methyl                                     5   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3,5Cl.sub.2 C.sub.6 H.sub.3                                                             CH.sub.3                                                                          H  200-202                                                                             ethanol                                                                              C.sub.12 H.sub.7                                                              Cl.sub.2 N.sub.3                                                              O.sub.3                    trione-2(2',5',dichlorophenyl)-7-methyl                                   6   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               4FC.sub.6 H.sub.4                                                                       CH.sub.3                                                                          H  197-198                                                                             ethanol                                                                              C.sub.12 H.sub.8                                                              FN.sub.3 O.sub.3           trione-2(4'-fluorophenyl)7-methyl                                         7   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               4CH.sub.3 C.sub.6 H.sub.4                                                               CH.sub.3                                                                          H  164-166                                                                             ethanol                                                                              C.sub.13 H.sub.11                                                             N.sub.3 O.sub.3            trione-2'(4'-tolyl)-7-methyl                                              8   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3,5(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                     CH.sub.3                                                                          H  203-205                                                                             ethanol                                                                              C.sub.14 H.sub.13                                                             N.sub.3 O.sub.3            trione-2(3',5',-dimethylphenyl)-7-methyl                                  9   Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3,5(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                   CH.sub.3                                                                          H  220-221                                                                             benzene                                                                              C.sub.14 H.sub.13                                                             N.sub.3 O.sub.3            trione-2(3',5',-dimethoxyphenyl)-7-methyl                                 10  Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               4NO.sub.2C.sub.6 H.sub.4                                                                CH.sub.3                                                                          H  226-228                                                                             ethanol                                                                              C.sub.12 H.sub.8                                                              N.sub.4 O.sub.5            trione-2(4-nitrophenyl)-7-methyl                                          11  Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3,5(CF.sub.3).sub.2 C.sub.6 H.sub.3                                                     CH.sub.3                                                                          H  146-148                                                                             ethanol                                                                              C.sub.14 H.sub.7                                                              F.sub.6 N.sub.3                                                               O.sub.3                    trione-2(3',5'-bis-trifluoromethyl-                                           phenyl)-7-methyl                                                          12  Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               CH.sub.3  CH.sub.3                                                                          H  116-117                                                                             ethanol                                                                              C.sub.7 H.sub.7                                                               N.sub.3 O.sub.3            trione-2,7-dimethyl                                                       13  Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               nC.sub.3 H.sub.7                                                                        nC.sub.3 H.sub.7                                                                  H  156-158                                                                             ethanol                                                                              C.sub.14 H.sub.11                                                             Cl.sub.2 N.sub.3                                                              O.sub.3                    trione-2(3',5'-dichlorophenyl)-                                               7n . propyl                                                               14  Pyrazolo[1,2-a][1,2,4]triazol-1,3,5-                                                               3,5Cl.sub.2 C.sub.6 H.sub.3                                                             CH.sub.3                                                                          C.sub.2 H.sub.5                                                                  144-145                                                                             ethanol                                                                              C.sub.14 H.sub.11                                                             Cl.sub.2 N.sub.3                                                              O.sub.3                    trione-2(3',5'-dichlorophenyl)-6-                                             ethyl-7-methyl                                                            __________________________________________________________________________                                   Com-                                                                              PERCENTUAL ANALYSIS                                                       pound                                                                             % C    % H    % N    % Cl                                                 No. Calc.                                                                            Found                                                                             Calc.                                                                            Found                                                                             Calc.                                                                            Found                                                                             Calc.                                                                            Found              __________________________________________________________________________                                   1   59.10                                                                            59.13                                                                             3.70                                                                             3.50                                                                              17.25                                                                            17.30                                                    2   51.91                                                                            51.84                                                                             2.90                                                                             2.79                                                                              15.13                                                                            15.14                                                                             12.77                                                                            12.83                                             3   51.91                                                                            51.57                                                                             2.90                                                                             2.71                                                                              15.13                                                                            15.20                                                                             12.77                                                                            12.67                                             4   46.18                                                                            46.29                                                                             2.26                                                                             2.14                                                                              13.46                                                                            13.33                                                                             22.72                                                                            22.79                                             5   46.18                                                                            46.30                                                                             2.26                                                                             2.13                                                                              13.46                                                                            13.75                                                                             22.72                                                                            22.51                                             6   55.0                                                                             54.85                                                                             3.06                                                                             3.05                                                                              15.55                                                                            15.75                                                    7   60.70                                                                            59.95                                                                             4.31                                                                             4.53                                                                              16.33                                                                            16.21                                                    8   61.99                                                                            61.42                                                                             4.83                                                                             4.87                                                                              15.49                                                                            15.58                                                    9   55.45                                                                            55.56                                                                             4.32                                                                             4.16                                                                              13.85                                                                            13.71                                                    10  50.01                                                                            50.37                                                                             2.80                                                                             2.89                                                                              19.44                                                                            19.14                                                    11                11.09                                                                            11.18                                                    12  46.41                                                                            46.83                                                                             3.89                                                                             3.85                                                                              23.20                                                                            23.43                                                    13  49.43                                                                            49.19                                                                             3.26                                                                             3.22                                                                              12.35                                                                            12.36                                                                             20.85                                                                            21.02                                             14  49.43                                                                            49.22                                                                             3.26                                                                             3.02                                                                              12.35                                                                            12.20                                                                             20.85                                                                            21.17              __________________________________________________________________________

The compounds of this invention act "in vitro" as well as "in vivo" toinhibit the growth of Botrytis cynerea.

The inhibiting action "in vitro" at a concentration of 100 p.p.m. isrecorded in the following Table II.

                  TABLE II                                                        ______________________________________                                        Fungicide activity "in vitro" against Botrytis Cynerea,                       expressed as inhibition of growth after 96h at 22° C.                  Com-                           Index                                          pound                          of activity                                    No.   Formula                  at 100 ppm*                                    ______________________________________                                               ##STR7##                3                                              2                                                                                    ##STR8##                2                                              3                                                                                    ##STR9##                3                                              4                                                                                    ##STR10##               2                                              5                                                                                    ##STR11##               3                                              6                                                                                    ##STR12##               2                                              7                                                                                    ##STR13##               1                                              8                                                                                    ##STR14##               3                                              13                                                                                   ##STR15##               3                                              ______________________________________                                         *Inhibition between 0 and 25% = 0; between 26 and 50% = 1; between 51 and     75% = 2; greater than 76% = 3.                                           

The pyrazolo-triazol-triones may be formulated according to knowntechniques, in the form of powders, wettable powders, aqueous emulsionsor suspension, solutions in organic solvents, possibly with the aid ofsurfactants, dispersants or diluents.

The following examples are given to illustrate the invention in moredetail, and are not intended to be limiting.

EXAMPLE 1 Pyrazolo[1,2-a][1,2,4]-triazol-1,3,5-trione-2-phenyl-7-methyl(Compound No. 1)

A mixture of 5.1 g of 2-carboxyethyl-3-methyl-3-pyrazolin-5-one, 3.6 gof phenylisocyanate and 3 g of triethylamine in 80 ml of anhydrousbenzene was heated for 7 hours at 50° C.

Thereupon, the solvent was removed by evaporation at reduced pressureand the residue was diluted with 150 ml of chloroform. The chloroformsolution was then washed twice with 30 ml of water. This latter wasrecovered as such by acidification of the combined aqueous extracts withdiluted hydrochloric acid and by successive filtering of the solid thatseparated (2.4 g).

From the chloroform solution, after anhydrification on sodium sulphate,and by evaporation of the solvent at reduced pressure, there wasobtained an oily residue which was repeatedly diluted with petroleumether. The low-melting solid thus obtained consisted of a mixture ofethyl phenylcarbamate and compound No. 1.

By crystallization from ethanol, there were obtained 1.7 grams ofcompound No. 1 with a melting point of 164°-166° C.

The IR analysis resulted: (in nujol) ν_(max). =1820, 1810, 1740, 1695,1585 cm⁻¹ ;

The NMR analysis: (CDCl₃)δ=7.4 (S, 5H, aromatics); 5.5 (S, 1H,unsaturated CH); 2.5 ##STR16##

Percent analyses: for C₁₂ H₉ N₃ O₃

Calculated %: C=59.10; H=3.70; N=17.25; Found %: C=59.13; H=3.50;N=17.30.

EXAMPLE 2Pyrazolo[1,2-a]-[1,2,4]-triazol-1,3,5-trione-2-(3',5'-dichlorophenyl)-7-methyl(Compound No. 5)

(a) Into a suspension consisting of 5.1 g of2-carboxyethyl-3-methyl-3-pyrazolin-5-one in 50 ml of anhydrous benzene,was dripped, at room temperature, a solution of 11.3 g of3,5-dichlorophenylisocyanate in 50 ml of anhydrous benzene and 3 g oftriethylamine.

The solution, after the addition of triethylamine, became clear and wasmaintained at 40°-45° C. for 4 hours. By cooling down to roomtemperature, there was obtained a solid which was then filtered andwashed with benzene.

Thereby were obtained 6 grams of a raw product having a melting point of195°-198° C., and which, crystallized from ethanol, yielded 5.4 grams ofcompound No. 5 in the form of crystals having a melting point of between200° and 202° C.

IR: (nujol) ν_(max) =1815, 1755, 1720, 1585, 1570 cm⁻¹

NMR: (CDCl₃) δ=7.5 (m, 3H, Aromatics; 5.6 (S, 1H, unsaturated CH); 2.6##STR17##

Mass: m/_(e) =311 (M⁺), 187 (M⁺ - ##STR18##

Analysis: for C₁₂ H₇ Cl₂ N₃ O₃

Calculated %: C=46.18; H=2.26; N=13.46; Cl=22.72; Found %: C=46.30;H=2.13; N=13.75; Cl=22.51.

(b) Reaction conducted on the above indicated quantities, keeping thesolution on reflux for 2.30 hours. The raw product, amounting to 5.6 g,with m.p.=195°-198° C., by crystallization from ethanol, yielded 5 g ofa product with a m.p. of 202° C.

(c) To a suspension of 3.4 g of2-carboxyethyl-3-methyl-3-pyrazolin-5-one in 40 ml of anhydrous benzene,under stirring and at room temperature, were added a solution of 3.8 gof 3,5-dichlorophenylisocyanate in 40 ml of anhydrous benzene and 2drops of triethylamine.

After 10 minutes, there separated a white, flaky precipitate, presumably1(3',5'-dichloro-phenylcarbamoyl)-2-carboxyethyl-3-pyrazolin-5-one. Tothe solution thus obtained were added 2 g of triethylamine. The solutionrapidly became clear and was then maintained at 45° C. for 3 hours.

The benzene was then evaporated at reduced pressure and the residue wasdiluted with 150 ml of chloroform. The solution was washed with water,then anhydrified on sodium sulphate and, finally, was evaporated atreduced pressure.

The raw residue thus obtained, after having been crystallized twice fromethanol, yielded 2.3 g of compound No. 5 that had a melting point=194°C., while its I.R. spectrum proved identical with that of the sampleobtained according to process (a).

EXAMPLE 3 Pyrazolo-[1,2-a][1,2,4]-triazol-1,3,5-trione-2,7-dimethyl.(Compound No. 12)

Into a suspension consisting of 6.8 g of2-carboxyethyl-3-methyl-3-pyrazolin-5-one in 100 ml of anhydrous benzenewere dripped 4.6 g of methylisocyanate and 4 g of triethylamine. Thebenzene solution became clear and was then kept at a temperature ofbetween 45° and 50° C. for 6 hours.

Thereafter, the solvent was removed at reduced pressure, the residue wasdiluted with 100 ml of chloroform and this latter was washed with 15 mlof water, and then anhydrified on sodium sulphate.

By evaporation of the solvent at reduced pressure, there were obtained 8g of a thick oil which, repeatedly diluted with petroleum ether, whencold, solidified. By crystallization from ethanol, there were obtained4.6 g of a white, crystalline solid with a melting point of 115°-117° C.(compound No. 12).

IR analysis: (nujol) ν_(max). =1815, 1740, 1675, 1580 cm⁻¹

NMR analysis: (CDCl₃) δ=5.5 (S, 1H, unsaturated CH); 3.13 (S, 3H,N--CH₃); 2.5 (S, 3H, CH₃ --C═)

Percent analysis: for C₇ H₇ N₃ O₃

Calculated %: C=46.41; H=3.89; N=23.20; Found %: C=46.53; H=3.85;N=23.43.

What is claimed is: 1.Pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-[2H]-triones having the generalformula ##STR19## in which R¹ is lower alkyl, phenyl, phenyl substitutedby lower alkyl, lower alkoxyl, trihalomethyl, NO₂ or halogen; andR² andR³, the same or different, are H or lower alkyl. 2.Pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-[2H]-triones according to claim1, in which R¹ is dihalophenyl. 3.Pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-trione-2-(3',5'-dichlorophenyl)-7-methyl.4.Pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-trione-2-(3'-chlorophenyl)-7-methyl.5.Pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-trione-2-(3'-5'-dimethylphenyl)-7-methyl.6.Pyrazolo-[1,2,a]-[1,2,4]-triazol-1,3,5-trione-2-(3',5'-dichlorophenyl)-7-n-propyl.7. Method for preventing infections by Botrytis cinerea on usefulplants, said method consisting in sprinkling the plants with thecompounds of claim 1, either as such or in the form of compositionscontaining said compounds, in quantities of at least 0.75% upward. 8.Compositions suited for fighting infections by Botrytis cinerea onuseful plants, said compositions containing an antibotrytical amount ofat least one compound according to claim 1, and being in the form of apowder, suspension, emulsion or solution.